Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones

Acceptance summary:

This paper probes the molecular mechanism by which bacteria use small molecules to co-ordinately multicellular responses. The range of the study from total synthesis of complex small molecules to structural studies of the signaling system were all well done. There is potential for future research, possibly with identification of the upregulated small molecule(s)

Decision letter after peer review:

Thank you for submitting your article "Biochemical Basis for the Regulation of Biosynthesis of Antiparasitics by Bacterial Hormones" for consideration by eLife. Your article has been reviewed by three peer reviewers, including Jon Clardy as the Reviewing Editor and Reviewer #1, and the evaluation has been overseen by Michael Marletta as the Senior Editor. The following individual involved in review of your submission has agreed to reveal their identity: Brian Bachman (Reviewer #2).

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.

We would like to draw your attention to changes in our revision policy that we have made in response to COVID-19 (https://elifesciences.org/articles/57162). Specifically, when editors judge that a submitted work as a whole belongs in eLife but that some conclusions require a modest amount of additional new data, as they do with your paper, we are asking that the manuscript be revised to either limit claims to those supported by data in hand, or to explicitly state that the relevant conclusions require additional supporting data.

Our expectation is that the authors will eventually carry out the additional experiments and report on how they affect the relevant conclusions either in a preprint on bioRxiv or medRxiv, or if appropriate, as a Research Advance in eLife, either of which would be linked to the original paper.

Summary:

Humans use small diffusible molecules – hormones and neurotransmitters – to coordinate multicellular responses, and bacteria use a functionally equivalent system – bacterial hormones in this manuscript – to coordinate cellular behavior. This study investigated one foundational signaling system in molecular and mechanistic detail to produce an informative description of how the bacterial hormone avenolide binds to its cognate receptor AvaR1 to regulate the production of other diffusible small molecules, some of which could be previously undescribed and conceivably therapeutically useful. The report clearly describes the studies in convincing and clear detail.

Essential revisions:

Both peer reviewers and the Reviewing Editor thought that the article contained convincing data on an important topic and that a suitably revised manuscript would be a worthy contribution to eLife. They also felt that the manuscript needed additional work in explaining the motivation for some studies and ideally additional experimental data. Specifically:

• The manuscript described a detailed structural study on an important regulator of small molecule biosynthesis with potential significance to the discovery of new molecules that might be useful therapeutic leads. The manuscript concludes with a demonstration of this potential that is, to put it bluntly, underwhelming: color changes that might indicate the production of previously cryptic molecules. There is no additional evidence to support this interpretation. No differential metabolomics that would indicate production of a new molecule, no evidence that the production of any new molecule was induced through AvaR1 regulation, not even evidence that there was a qualitative, not quantitative, change in metabolism were presented.

• The manuscript would benefit from a clearer description of why avenolide was synthesized and why the strategy was significant. A 22-step synthesis is not something undertaken lightly. Was it synthesized because that was the most efficient way to get the desired ligand? Was it synthesized because eventually a synthesis combined with the structural data could lead to the design and synthesis of new activating ligands for different R-proteins?

Revisions expected in follow-up work:

In the event you are not able to provide more substantial proof of the ability/potential to discover new molecules to the current manuscript, we would suggest deleting the color change experiments. They by themselves actually undercut the significance of the present manuscript.